Preparation method of montelukast chiral intermediate

Abstract

The invention discloses a preparation method of a montelukast chiral intermediate, which belongs to the field of medical chemical synthesis. The preparation method comprises the following steps of: reacting compound S1 serving as the raw material with methylmagnesium chloride, oxidizing by using manganese dioxide, chlorinating by using NCS (Succinchlorimide), carrying out chiral reduction by using (-)-B-chlorodiisopinocampherylborane, carrying out cyclization under the action of anhydrous potassium carbonate, and carrying out addition reaction with 2-methyl formate benzylmagnesium bromide to obtain the medical intermediate S7. By adopting the preparation method disclosed by the invention, the application of precious metal for catalysis is avoided, the reaction conditions are mild and easily controlled, the reaction product is single, the yield is high, the optical purity and the chemical purity of the product are greatly improved, the process is simple, the raw materials are low in price and easily available, and therefore the preparation method is more suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to the field of medical chemical synthesis. Background technique [0002] The chemical name of Montelukast Sodium is: [0003] 1-(((1-(R–(3-(2-(7-chloro-2-quinolinyl)-vinyl)-phenyl)-3-(2-hydroxy-1-methylethyl) -phenyl) propyl) mercapto) methyl) sodium cyclopropyl acetate, the structural formula is as follows: [0004] [0005] It is a new type of highly selective LTD4 receptor antagonist developed by Merck Company of the United States, and its trade name is Singulair [0006] (Singular), first launched in Finland and Mexico in February 1998, in the UK and the US in April and October of the same year, and subsequently in 71 countries including Canada, Italy, Spain, Sweden, Switzerland, Germany and France. As a selective leukotriene LTD4 receptor antagonist, the drug can selectively bind to the leukotriene LTD4 receptor on the respiratory mucosa, block the action of allergic mediators, improve respiratory inflammation, and mak...

AI Technical Summary

Problems solved by technology

[0010] But there are two key problems in this route: 1. The preparation of vinylmagnesium bromide is relatively difficult, and the quality of the reagent has a great influence on the reaction; In the process, it is easy to be poisoned and inactivated, and the recovery rate is low. On the other hand, during the reaction process, hydroiodide is formed to wrap Pd / C, resulting in very slow conversion of raw materials in the later stage of the reaction.

The use of precious metal catalysis, expensive raw materials, and harsh reaction conditions are a serious bottleneck for industrial mass production

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